Gastrointestinal stromal tumors. Pathogenetic mechanisms, phenotypic characterization and prognosis

Sammanfattning: Gastrointestinal stromal tumor (GIST), the most common non-epithelial neoplasm of the gastrointestinal tract, has historically been problematic both conceptually and clinically. Recently, GIST has been shown to share phenotypic features with the interstitial cells of Cajal (ICC), including the almost uniform expression of the tyrosine kinase receptor KIT. GIST have frequently been found to have activating mutations of the KIT gene or more rarely the platelet derived growth factor receptor alpha (PDGFRA) gene; these apparently play a key role in GIST s pathogenesis. The occurrence of GIST lacking KIT and PDGFRA mutations indicates, however, that alternative pathogenetic mechanisms exist. Clinical studies regarding the correlation of mutations with disease outcome in GIST have been contradictory. Mutation analysis of the KIT gene in 14 GIST revealed exon 11 mutations in 9 tumors. Mutations were detected in benign as well as malignant GIST. Cytogenetic and SKY analyses revealed several recurrent structural and numerical abnormalities; losses of 1p, 14 and 22 being the most common. No correlation was found between biologic behavior, KIT mutation status and chromosome aberrations. All tumors preferentially expressed the shorter, tumorigenic, splice variant of exon 9 of the KIT gene.Imatinib mesylate, a new designer drug, selectively inhibits type III receptor tyrosine kinases and has a dramatic, anti-tumor effect on GIST. In a center-based study of 17 patients with GIST, we studied the relationship between KIT exon 11 mutation status and treatment response. Imatinib was especially effective in tumors with exon 11 mutations - KIT exon 11 mutations were detected in 8 of 9 patients with partial response, whereas no mutations were detected in 3 patients with stable or progressive disease.Earlier studies of receptor tyrosine kinase mutations indicate that different types of mutations are associated with distinctive phenotypes and potentially clinical behavior in GIST. In a large, retrospective, population-based series of GIST from the pre-imatinib mesylate era, we examined whether mutation type correlated with phenotype and clinical course. KIT exon 11 mutations were detected in GIST from 117 of 233 patients (69 deletions, 27 missense mutations and 21 duplications). The deletion subgroup had a significantly decreased disease-free survival. KIT exon 11 deletions were found to be an independent adverse prognostic factor with respect to disease-free survival. GIST have been reported to occasionally occur in patients with neurofibromatosis type I (NF1). NF1 is the most common autosomal dominant inherited disorder, with an incidence of 1/3-4000 individuals. The clinical spectrum of NF1 is extremely wide and includes organic as well as mental manifestations. We analyzed GIST arising in 15 NF1 patients and found that this subset of GIST has a unique phenotype, including an almost uniformly benign appearance histologically, a propensity for multicentricity, association with ICC hyperplasia, predominant location in the small intestine, and a spindle cell morphology as well as benign or very low grade malignant behavior. The NF1-associated GIST also have a unique genotype in that they lack KIT and PDGFRA mutations, indicating that different pathogenetic mechanisms are involved in their evolution.In summary, we have shown that the role of KIT mutations in the biological behavior of GIST is more complex than previously recognized and that the type of mutation influences clinical behavior as well as response to imatinib treatment. NF1-associated GIST are a pheno- and genotypically unique subset of GIST that lack activating mutations in the KIT and PDGFRA genes.